tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

HER2 activating mutations occur in 2% to 3% of HER2-nonamplified breast cancers with a higher incidence in lobular cancers. Ma and colleagues demonstrate the pan-HER inhibitor neratinib is active in this setting with a clinical benefit rate of 31% in advanced disease. Retrospective analysis of plasma-circulating tumor DNA (ctDNA) showed a high specificity and good sensitivity for detecting HER2 mutations. An early decrease in ctDNA HER2 mutation variant allele frequency correlated well with clinical responsiveness. This study therefore establishes ctDNA sequencing as a noninvasive approach to HER2 mutation diagnosis, simplifying patient eligibility assessment, and potentially disease monitoring.Despite a considerable risk of recurrence, a widely accepted adjuvant treatment for early-stage melanoma is lacking. Notwithstanding the advent of immune checkpoint inhibitors, distant recurrences will still prove fatal for many patients. Koster and colleagues show that local low-dose CpG-B administration provides an adjuvant treatment option for early stages of melanoma that selectively activates lymph node-resident dendritic cells, boosts loco-regional and systemic T-cell immunity, and can offer durable protection against recurrence with minimal side effects. This one-off and generally applicable intervention could eventually preempt the need for often toxic and costly systemic treatment with immune checkpoint inhibitors.Cisplatin, a commonly prescribed chemotherapeutic, can lead to persistent and debilitating neurotoxicity. Dolan and colleagues show that cisplatin-induced peripheral neuropathy (CisIPN) symptoms are common, significantly correlated with weight gain since treatment, and inversely correlated with self-reported health and physical activity. Furthermore, the authors identified age, tobacco use, excess drinking, and hypertension as significantly associated with CisIPN. They found high trait heritability, indicating that genetic variants likely explain a large proportion of variability in the CisIPN phenotype. The authors found RPRD1B, a DNA repair gene, to be protective against neuropathy induced by various drugs, indicating that it might play a broad neuroprotective role.It is widely accepted that tissue tumor mutational burden can help predict response to checkpoint inhibitor immunotherapy. In assessing peripheral blood circulating tumor DNA of patients with a wide variety of malignancies, Khagi and colleagues found that bright line cutoffs for total and variant of unknown significance (VUS) alteration number predicted response rate, progression-free, and overall survival to checkpoint inhibitor-based immunotherapy. This analysis demonstrates a correlation between high alteration number in blood-derived circulating tumor DNA and favorable outcome, providing the impetus to potentially utilize liquid biopsy as a noninvasive predictive biomarker for checkpoint inhibitor response across various histologies.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

HDAC inhibitors have been shown to modulate immune response in preclinical models. To explore the immunomodulatory activity of HDAC in the clinical setting, Pili and colleagues designed a phase I/II clinical study with the selective class I inhibitor entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma. The combination resulted in greater objective response rate and increased median progression-free survival compared to historical data. This proof of principle provides the rationale for further clinical testing of this epigenetic modulator and immunotherapies as rational combination strategies.PARP inhibitors (PARPi) have emerged as an intriguing treatment strategy for patients with Ewing sarcoma (ES), but have yet to demonstrate responses in clinical trials. Heske and colleagues performed a high-throughput matrix drug screen to identify novel, synergistic drug combinations in ES and found that combining PARPi with NAMPT inhibitors, which block the rate-limiting step in NAD+ production, was a rational approach to enhancing PARP inhibition. This combination resulted in robust synergy in vitro through decreased PAR activity and increased DNA damage, and retained efficacy in vivo, suggesting that this combination may be a promising strategy for ES.Hu and colleagues identify a novel application of plasma cell-free DNA (cfDNA) genotyping, widely used as a cancer diagnostic, to study the germline genetics of cancer patients. Germline and somatic EGFR T790M mutations are used as a clinical model to develop methods for differentiating germline and somatic variants within plasma cfDNA. Using a database of 31,414 subjects undergoing plasma next-generation sequencing (NGS), they demonstrate that germline EGFR T790M mutations are enriched in lung cancer, but not other cancer types. Awareness is needed of the potential for clinically important incidental germline findings from plasma NGS.Hyperactivation of the Wnt/β-catenin and PI3K/Akt signaling pathways has limited clinical benefit mostly due to unknown resistance mechanisms and the lack of predictive biomarkers of the drug response. Kang and colleagues investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via ICAT, a negative regulator of Wnt/β-catenin signaling. The authors provide evidence for a rational stratification of patients hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways using PLD1 and ICAT as predictive targets of the drug response. These results may assist in the clinical development of a PLD1 inhibitor for treatment of CRC patients carrying APC and PI3KCA mutations.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA double strand breaks. Ovarian cancer (OC) patients who carry BRCA2 germline mutation and are treated with platinum had prolonged survival. Through two independent cohorts, Labidi-Galy and colleagues investigated the correlation between BRCA2 genotype and OC patients’ survival, according to the location of mutations in the functional domains of the protein. They observed that among BRCA2 carriers, those having mutations located in the RAD51-binding domain (exon 11) have prolonged progression-free survival, platinum-free interval, and overall survival. These results have implications for personalized therapy in BRCA carriers.Chemotherapy resistance represents a significant barrier to acute myeloid leukemia (AML) therapy. Lee and colleagues demonstrate that double negative T cells (DNT) from healthy individuals can be expanded ex vivo to therapeutic levels under GMP conditions and can be cryopreserved. Expanded human DNTs target a large array of primary AML cells, including chemotherapy-resistant patient samples in vitro and significantly reduce the leukemia load in patient-derived xenograft models in a DNT donor unrestricted manner. Importantly, allogeneic DNTs do not attack normal human cells or cause xenogeneic GVHD. Collectively, healthy donor-derived allogeneic DNTs provide a potential new cellular therapy that is safe and effective to treat patients with chemotherapy-resistant AML.Small cell lung cancer (SCLC) is incurable in most cases, and the absence of distinct kinase addictions has precluded effective targeted therapies. BCL-2 has emerged as an effective drug target in SCLC, but clinical trials with the BCL-2/BCL-xL inhibitor, navitoclax, were complicated by its ability to inhibit BCL-xL, which resulted in dose-dependent thrombocytopenia in SCLC patients. Lochmann and colleagues demonstrate that inhibiting only BCL-2 with the FDA-approved BCL-2 pure inhibitor, venetoclax, is sufficient to induce anti-SCLC activity in a subset of high BCL-2-expressing cell lines and patient-derived xenograft models, suggesting venetoclax as a promising therapeutic in SCLC patients with high-BCL2.Richardson and colleagues sought to determine whether the canonical EMT marker, vimentin, has a functional role in lung adenocarcinoma metastasis. A novel, genetically engineered mouse model was created that lacks vimentin in a clinically-relevant metastatic lung cancer background. The model revealed that vimentin is necessary for efficient metastasis via heterotypic tumor cell-cancer-associated fibroblast (CAF) interactions. The 3D in vitro studies show that vimentin-positive CAFs are required to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion. Similar interactions and expression are observed in human lung adenocarcinoma, suggesting that vimentin targeting could reduce metastasis by inhibiting collective invasion.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation requires novel strategies. Khouri and colleagues show that the addition of lenalidomide to ipilimumab at 3 mg/kg for just two cycles can induce greater than expected and durable clinical responses. This impact also is suggested by the additive increased numbers of inducible costimulatory +CD4+ T cells by lenalidomide. The preliminary data indicate similar immune responses in the allogeneic and autologous transplant recipients. The treatment is safe, with no severe treatment-related toxicities, minimal immune-mediated toxicity and no graft-versus-host disease. Findings from this study support further investigation of this combination in this setting.Barrett's esophagus can be diagnosed and biopsied by esophagogastroduodenoscopy, but current screening and surveillance strategies are limited by the absence of specific imaging markers predictive of increased risk for esophageal adenocarcinomas (EAC). Fang and colleagues use a Barrett's esophagus mouse model and EAC patient data to demonstrate that the chemokine receptor 4 (CXCR4) is upregulated in the immune tumor microenvironment, thus presenting a highly attractive target for PET/CT imaging using CXCR4-targeted probes. These findings provide new insights into the kinetics and pathogenesis of EAC and introduce CXCR4-based imaging of the tumor microenvironment as a potential approach for diagnosis and surveillance of EAC.RAS-mutant cancer is difficult to treat with standard care. Nonsteroidal anti-inflammatory drugs like aspirin have been proposed to reduce cancer burden. Hammerlindl and colleagues describe combining aspirin with sorafenib, a multi-kinase inhibitor, in RAS-mutant melanoma and lung cancer. The combination induced activation of both AMPK and ERK pathways, leading to strongly enhanced tumor cytotoxicity at relatively low sorafenib doses. Combining aspirin and sorafenib is a viable treatment strategy in refractory and relapsed RAS-mutant cancer.Effective therapies for glioblastoma, a cancer known to being highly resistant to chemotherapy, may have to target multiple tumor cell survival mechanisms. Su and colleagues investigated the mechanisms of action of TG02, a novel CDK9 inhibitor, as a single agent and in combination with temozolomide, utilizing in vitro and in vivo glioblastoma models. In addition to transcriptional suppression, TG02 also was found to induce mitochondrial dysfunction, glycolytic suppression, and, when combined with temozolomide, synergistically decreased energy production in glioblastoma. These results have led to an ongoing clinical trial investigating this promising therapeutic strategy in patients with recurrent glioblastomas (NCT02942264).
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Disease recurrence after curative resection for hepatocellular carcinoma (HCC) patients remains the major cause for dismal outcome. Results from this large-sample prospective randomized controlled trial showed that adjuvant transarterial chemoembolization (TACE), along with adriamycin and lipiodol, can significantly reduce tumor recurrence, improve recurrence-free survival and overall survival for HBV-related HCC patients with an intermediate or high risk of HCC recurrence after curative liver resection. The data also suggests that adjuvant TACE decreases HCC recurrence after curative liver resection by eradicating pre-existing microscopic tumor foci that traditional imaging modalities fail to detect in the perioperative stage and is well tolerated.In clinical practice, no validated biomarkers are currently available to predict the efficacy of pemetrexed plus platinum doublet chemotherapy for nonsquamous NSCLC patients. This study investigated the metabolic characteristics of 354 prechemotherapeutic serum samples and found tight associations between small metabolites and the responses of patients to this cytotoxic drug combination. An effective discriminant model was developed by employing a seven-metabolite panel, which can predict the efficacy of the chemotherapeutic regimens, prior to treatment, with a sensitivity of 90.8% and specificity of 79.5%. This serum-based biomarker study can be easily applied in clinical practice and personalize treatment decisions.Successful implementation of HPV screening requires triage to distinguish transforming from benign HPV infections. Previous studies have shown associations of HPV DNA methylation with cervical precancer for some HPV types. In this study, Clarke and colleagues observed strong associations of increased methylation with precancer in all 12 carcinogenic HPV types, suggesting that DNA methylation is a general phenomenon in the transition from HPV infection to precancer. HPV methylation showed good risk stratification and better performance than current triage methods. A multi-type methylation assay may solve the current problem of how to manage HPV-positive women, in high- and low-resource settings.The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across 32 different cancer types involving multiple molecular levels. Chen and colleagues applied an alternative molecular classification approach to over 10,000 tumor samples to define ten major pan-cancer “classes” that transcended tissue or histology distinctions. Coordinate pathways and processes were revealed across these pan-cancer classes, and the influence of the tumor microenvironment was evident within distinct subsets of human tumors. One molecular class manifesting a differential expression profile of neuroendocrine tumors could have therapeutic implications for an appreciable subset of human cancers.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

The identification of biomarkers that can predict therapeutic outcomes in response to PD-1 or PD-L1 immune checkpoint inhibitors remains an unmet need in the treatment of NSCLC and urothelial cancer. To identify a predictive biomarker for durvalumab, an anti-PD-L1 monoclonal antibody, Higgs and colleagues performed RNA sequencing of biopsies from NSCLC and urothelial cancer patients enrolled in a nonrandomized phase Ib/II clinical trial (NCT01693562). Their results demonstrate that gene expression levels of four IFNγ-inducible mRNAs correlate with improved clinical outcomes in durvalumab-treated patients with NSCLC or urothelial cancer. This IFNγ gene signature may augment the predictive value of PD-L1 and other biomarkers in identifying those cancer patients who are most likely to respond to therapy with durvalumab or other immune checkpoint inhibitors, independently of PD-L1 assessed by immunohistochemistry.To determine whether the 21-gene recurrence score can predict benefit of postmastectomy radiotherapy (PMRT) in women with ER-positive T1-2 N1 breast cancer, Goodman and colleagues performed an observational cohort study using the National Cancer Database as a discovery cohort and the SEER registry as a validation cohort. Women with low-risk recurrence scores derived a significant survival benefit from PMRT, while women with intermediate- and high-risk scores did not. Women at the lowest risk of distant failure may, therefore, derive the greatest benefit from aggressive locoregional therapy with PMRT.The poor response of advanced stage ovarian clear cell carcinoma (OCCC) towards platinum-based chemotherapy urges alternative therapeutic strategies. Caumanns and colleagues performed a comprehensive kinome-wide screen in a large set of OCCC patients and reported numerous genomic alterations related to mTORC1/2 activation. Ubiquitous expression of mTORC1/2 downstream target p-S6 in OCCC patients and the high sensitivity of OCCC cell lines and patient-derived xenografts to mTORC1/2 inhibitors indicate the clinical relevance of these genomic alterations. These findings propose further exploration of mTORC1/2 inhibitors, currently being evaluated in phase II clinical trials in OCCC patients.Epithelial-to-mesenchymal transition (EMT) plays a critical role in tumor invasion and metastasis. Integrating findings from a human papillomavirus-16 E6/E7 oncoprotein driven model of invasion with analysis of patient samples and TCGA RNA-seq, Srivastava and colleagues identify Slug as the major modulator of EMT in head and neck squamous cell carcinoma (HNSCC). Expression of the p63 isoform ΔNp63γ is necessary and sufficient to induce Slug and EMT, which requires signaling through the activity of another p63 target Src. Elevated expression of Src associates with worse outcome in HNSCC; thus clinical efforts targeting Src hold promise in poor prognosis HNSCC.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Inflammation is a key driver of oncogenesis. Using complimentary in vitro and in vivo studies, Ayers and colleagues identify a role for potent pro-inflammatory mast cells (MCs) in inflammatory-driven Kaposi Sarcoma (KS). MCs are closely associated with spindle cells, extensively activated to degranulate, and infected by KSHV in patient tumors. Patients display signs of extensive MC activation, including elevated plasma levels of histamine and tryptase. Successful treatment of an AIDS-KS patient with anti-MC therapy underscored their clinical importance. These data strongly suggest a specific role for MCs in KSHV-driven oncogenesis and identify MC antagonists as a promising novel, pathogenesis-targeted, therapeutic approach to KS.Crohn's disease (CD) can form precursor lesions, which harbor a risk to becoming colorectal cancer (CRC). The distinction of these precursors from sporadic adenoma or non-neoplastic inflamed mucosa is crucial for proper patient guidance; however, histology and endoscopy are unreliable and exhibit only low inter-observer agreement. Hirsch and colleagues identified TP53 mutations, aneuploidy and gains of chromosome arm 5p as early and frequent changes in CD to CRC progression. Gains of 5p were a distinctive feature of CD-related carcinogenesis and offer, together with TP53 mutation determination, an easily applicable tool for identifying high risk precursor lesions in CD.Erb-B2 receptor tyrosine kinase 2 (ERBB2) mutations have been identified across a wide range of cancers, but many of the mutations are still variants of unknown significance. Nagano and colleagues comprehensively assessed the transforming activities and drug sensitivities of 55 nonsynonymous ERBB2 mutations using the mixed-all-nominated-in-one (MANO) method. This study identified several ERBB2 mutations as activating mutations that showed varying sensitivities to ERBB2-targeted inhibitors. Thus, the MANO method might be beneficial for the determination of the best treatment for cancers harboring ERBB2 mutations and offer a fundamental database to help customize therapy for ERBB2-driven cancers.Cheung and colleagues demonstrate that the folate transporter and tumor-associated antigen folate receptor alpha (FRα) is overexpressed by aggressive high-grade triple-negative breast cancers (TNBC) and postneoadjuvant chemotherapy residual tumors. FRα is associated with poor clinical outcomes, and it participates in cancer cell signaling and growth through Src and ERK signaling. FRα and the folate cascade could be targeted with specific inhibitor drugs. Both antibody immunotherapy priming Fc-mediated antitumor immune responses, and antibody-drug conjugate treatment delivering a Src pathway inhibitor to FRα-expressing cells, significantly impaired TNBC growth, thus suggesting potential new therapeutic strategies for biological subsets of TNBC with poor prognosis.
Highlights of This Issue
Journal: Clinical Cancer Research (2018)

Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. To establish the origins of resistance mutations, Schmitt and colleagues integrated single-molecule duplex sequencing of Philadelphia-positive leukemias with computational simulations. A combination of drug target mutation burden and tumor-initiating cell fraction predicts the likelihood of preexisting resistance mutations. Compound resistance is unlikely to exist before therapy, but rather is predicted to arise following the failure of first-generation therapies. The results predict that front-line use of pan-target therapies (i.e., therapies that can overcome any single resistance mutation) could improve outcomes.Correlation of HER2 expression to therapeutic resistance was previously investigated on ex vivo models by others. To explore the role of dynamic status of HER2 on tumor cells, Li and colleagues performed HER2-iFISH to longitudinally examine constant variation of HER2 phenotype and chromosome aneuploidy in CTCs in gastric cancer patients. Comparing to low positivity of histopathologic detection of HER2 in tumor mass, significantly higher positivity (&gt;70%) of HER2 expression on aneuploid CTCs was demonstrated, which was relevant to developing resistance to the targeted and/or chemotherapy and thus shows promise to monitor developing therapeutic resistance in real time.Anti-PD-1/PD-L1-based immunotherapies can be transformative in a subset of metastatic cancer patients, but reliable biomarkers of response have been elusive. To integrate biomarkers of efficacy in clinical practice, Johnson and colleagues performed quantitative, multiplexed immunofluorescence tests comprised of HLA-DR, IDO-1, PD-1, and PD-L1 utilizing novel AQUA algorithms on archival, pre-treatment samples from 166 metastatic melanoma patients treated with PD-1 blockers across ten cancer centers. Biomarker signature-positive patients experienced superior survival and response rates in both discovery and validation cohorts. This two-slide assay on archival tissue may help identify patients who will have excellent outcomes with anti-PD-1 therapy.Pancreatic cancer is one of the biggest clinical challenges. Zhou and colleagues used a combination of local photothermal therapy and intratumoral application of an immunoadjuvant to treat a metastatic pancreatic tumor in mice, both subcutaneously and orthotopically. This unique combination significantly prolonged the animal survival time and slowed and, in many cases, prohibited the distant metastases. It also induced a long-term, tumor-specific immunity by increasing the quantity and quality of splenic and tumor-infiltrating antitumor T cells. This novel approach with its successful treatment results, particularly on orthotopic pancreatic tumors, shows promise as a clinical treatment modality for pancreatic cancer patients.